Nasal delivery devices

ABSTRACT

A nasal delivery device for and method of delivering substance to a nasal airway of a subject, the delivery device comprising: a nosepiece (117) for fitting to a nasal cavity of a subject, a mouthpiece (119) into which the subject in use exhales; a delivery unit, which comprises an actuation part which is manually displaceable to actuate the delivery unit to deliver substance from the nosepiece; and a valve assembly (127) which is fluidly connected to the nosepiece and the mouthpiece, wherein the valve assembly comprises a body element (128) and a valve element (131) which is movably disposed to the body element between closed and open configurations by manual displacement of the actuation part of the delivery unit to provide for an air flow through the nosepiece simultaneously with delivery of substance.

The present invention relates to a nasal delivery device for and amethod of delivering a substance, in particular one of a liquid, as asuspension or solution, or a powder, such as containing a medicament,especially systemic or topical pharmaceuticals, or a vaccine, to thenasal airway of a subject.

Referring to FIG. 10, the nasal airway 1 comprises the two nasalcavities separated by the nasal septum, which airway 1 includes numerousostia, such as the paranasal sinus ostia 3 and the tubal ostia 5, andolfactory cells, and is lined by the nasal mucosa. The nasal airway 1can communicate with the nasopharynx 7, the oral cavity 9 and the lowerairway 11, with the nasal airway 1 being in selective communication withthe anterior region of the nasopharynx 7 and the oral cavity 9 byopening and closing of the oropharyngeal velum 13. The velum 13, whichis often referred to as the soft palate, is illustrated in solid line inthe closed position, as achieved by providing a certain positivepressure in the oral cavity 9, such as achieved on exhalation throughthe oral cavity 9, and in dashed line in the open position.

There are many nasal conditions which require treatment. One suchcondition is nasal inflammation, specifically rhinitis, which can beallergic or non-allergic and is often associated with infection andprevents normal nasal function. By way of example, allergic andnon-allergic inflammation of the nasal airway can typically effectbetween 10 and 20% of the population, with nasal congestion of theerectile tissues of the nasal concha, lacrimation, secretion of waterymucus, sneezing and itching being the most common symptoms. As will beunderstood, nasal congestion impedes nasal breathing and promotes oralbreathing, leading to snoring and sleep disturbance. Other nasalconditions include nasal polyps which arise from the paranasal sinuses,hypertrophic adenoids, secretory otitis media, sinus disease and reducedolfaction.

In the treatment of certain nasal conditions, the topical administrationof medicaments is preferable, particularly where the nasal mucosa is theprime pathological pathway, such as in treating or relieving nasalcongestion. Medicaments that are commonly topically delivered includedecongestants, anti-histamines, cromoglycates, steroids and antibiotics.At present, among the known anti-inflammatory pharmaceuticals, topicalsteroids have been shown to have an effect on nasal congestion. Topicaldecongestants have also been suggested for use in relieving nasalcongestion. The treatment of hypertrophic adenoids and chronic secretoryotitis media using topical decongestants, steroids and anti-microbialagents, although somewhat controversial, has also been proposed.Further, the topical administration of pharmaceuticals has been used totreat or at least relieve symptoms of inflammation in the anteriorregion of the nasopharynx, the paranasal sinuses and the auditory tubes.

Medicaments can also be systemically delivered through the nasalpathway, the nasal pathway offering a good administration route for thesystemic delivery of pharmaceuticals, such as hormones, for example,oxytocin and calcitonin, and analgetics, such as anti-migrainecompositions, as the high blood flow and large surface area of the nasalmucosa advantageously provides for rapid systemic uptake.

Nasal delivery is also expected to be advantageous for theadministration of medicaments requiring a rapid onset of action, forexample, analgetics, anti-emetics, insulin, anti-epileptics, sedativesand hypnotica, and also other pharmaceuticals, for example,cardio-vascular drugs. It is envisaged that nasal administration willprovide for a fast onset of action, at a rate similar to that ofinjection and at a rate much faster than that of oral administration.Indeed, for the treatment of many acute conditions, nasal administrationis advantageous over oral administration, since gastric stasis canfurther slow the onset of action following oral administration.

It is also expected that nasal delivery could provide an effectivedelivery route for the administration of proteins and peptides asproduced by modern biotechnological techniques. For such substances, themetabolism in the intestines and the first-pass-effect in the liverrepresent significant obstacles for reliable and cost-efficientdelivery.

Furthermore, it is expected that nasal delivery using the nasal deliverytechnique of the present invention will prove effective in the treatmentof many common neurological diseases, such as Alzheimer's, Parkinson's,psychiatric diseases and intracerebral infections, where not possibleusing existing techniques. The nasal delivery technique of the presentinvention allows for delivery to the olfactory region, which region islocated in the superior region of the nasal cavities and represents theonly region where it is possible to circumvent the blood-to-brainbarrier (BBB) and enable communication with the cerebrospinal fluid(CSF) and the brain.

Also, it is expected that the nasal delivery technique of the presentinvention will allow for the effective delivery of vaccines.

Aside from the delivery of medicaments, the irrigation of the nasalmucosa with liquids, in particular saline solutions, is commonlypractised to remove particles and secretions, as well as to improve themucociliary activity of the nasal mucosa. These solutions can be used incombination with active pharmaceuticals.

For any kind of drug delivery, accurate and reliable dosing isessential, out it is of particular importance in relation to theadministration of potent drugs which have a narrow therapeutic window,drugs with potentially serious adverse effects and drugs for thetreatment of serious and life-threatening conditions. For someconditions, it is essential to individualize the dosage to theparticular situation, for example, in the case of diabetes mellitus. Fordiabetes, and, indeed, for many other conditions, the dosage of thepharmaceutical is preferably based on actual real-time measurements.

Currently, blood samples are most frequently used, but the analysis ofmolecules in the exhalation breath of subjects has been proposed as analternative to blood analysis for several conditions. Breath analysis iscurrently used for the diagnosis of conditions such as Helicobacterpylori infections which cause gastric ulcers.

WO-A-2000/051672 discloses a delivery device for delivering a substance,in particular a medicament, in a bi-directional flow through the nasalcavities, that is, an air flow which passes into one nostril, around theposterior margin of the nasal septum and in the opposite direction outof the other nostril. This bi-directional air flow advantageously actsto stimulate the sensory nerves in the nasal mucosa, therebyconditioning the subject for the delivery and providing a morecomfortable delivery situation.

It is an aim of the present invention to provide nasal delivery devicesand methods for delivering substances to a nasal cavity of subject, andin particular relatively-simple mechanically-actuatable deliverydevices.

In one aspect the present invention provides a nasal delivery device fordelivering substance to a nasal airway of a subject, comprising: anosepiece for fitting to a nasal cavity of a subject; a mouthpiece intowhich the subject in use exhales; a delivery unit, which comprises anactuation part which is manually displaceable to actuate the deliveryunit to deliver substance from the nosepiece; and a valve assembly whichis fluidly connected to the nosepiece and the mouthpiece, wherein thevalve assembly comprises a body element and a valve element which ismovably disposed to the body element between closed and openconfigurations by manual displacement of the actuation part of thedelivery unit to provide for an air flow through the nosepiecesimultaneously with delivery of substance.

In another aspect the present invention provides a method of deliveringsubstance to a nasal airway of a subject, comprising the steps of:fitting a nosepiece to a nasal cavity of a subject; the subject exhalinginto a mouthpiece; providing a delivery device which comprises: adelivery unit, which comprises an actuation part which is manuallydisplaceable to actuate the delivery unit to deliver substance from thenosepiece; and a valve assembly which is fluidly connected to thenosepiece and the mouthpiece, wherein the valve assembly comprises abody element and a valve element which is movably disposed to the bodyelement between closed and open configurations by manual displacement ofthe actuation part of the delivery unit; and manually displacing theactuation part of the delivery unit to move the valve element of thevalve assembly relative to the body element of the valve assemblybetween closed and open configurations and provide an air flow throughthe nosepiece simultaneously with delivery of substance.

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIGS. 1(a) and (b) illustrate a perspective view of a nasal deliverydevice in accordance with a first embodiment of the present invention;

FIG. 2 illustrates an exploded perspective view of the delivery deviceof FIG. 1;

FIG. 3 illustrates a vertical sectional view of the delivery device ofFIG. 1, in the at rest, non-actuated configuration;

FIG. 4 illustrates a vertical sectional view of the delivery device ofFIG. 1, in the actuated configuration;

FIG. 5 illustrates an exploded, fragmentary vertical sectional view ofthe delivery device of FIG. 1, in the actuated configuration;

FIGS. 6(a) to (c) illustrate the opening of the sealing member of thevalve assembly by operation of the delivery unit of the delivery deviceof FIG. 1;

FIG. 7 illustrates plots of the flow rates at the nosepiece and themouthpiece and the pressure at the mouthpiece for one exemplary device;

FIGS. 8(a) and (b) illustrate fragmentary vertical sectional views inthe at rest, non-actuated and actuated configurations of a nasaldelivery device in accordance with a second embodiment of the presentinvention;

FIGS. 9(a) and (b) illustrate fragmentary vertical sectional views inthe at rest, non-actuated and actuated configurations of a nasaldelivery device in accordance with a third embodiment of the presentinvention; and

FIG. 10 schematically illustrates the anatomy of the upper respiratorytract of a human subject.

FIGS. 1 to 7 illustrate a manually-actuated nasal delivery device inaccordance with a first embodiment of the present invention.

The delivery device comprises a housing 115, a nosepiece 117 for fittingin a nasal cavity of a subject, a mouthpiece 119 into which the subjectin use exhales, such as to enable delivery of an air flow into andthrough the nasal airway of the subject on exhalation by the subjectthrough the mouthpiece 119, and a delivery unit 120, which is manuallyactuatable to deliver substance to the nasal cavity of the subject.

The housing 115 comprises a body member 121, in this embodiment ofsubstantially elongate, tubular section which includes an aperture 123at one end thereof, through which projects an actuating part of thedelivery unit 120, in this embodiment as defined by the base of asubstance-containing chamber 173 of a substance-supply unit 169.

In this embodiment the body member 121 comprises two body sections 121a, b which are fixed together.

In this embodiment the body sections 121 a, b include inter-engaginglugs 124 and detents 125, here of snap-fit type, and sealing elements126, which act to close the air flow paths at the junctions of the bodysections 121 a, b.

In this embodiment the sealing elements 126 are adhesively bonded, butcould alternatively be mechanically bonded, such as by welding.

In an alternative embodiment the sealing elements 126 could be omitted.

The housing 115 further comprises a valve assembly 127 which is fluidlyconnected to the nosepiece 117 and the mouthpiece 119, and operablebetween closed and open configurations, as illustrated in FIGS. 3 and 4,such as to provide for an air flow, in this embodiment in the form of aburst of air, through the nosepiece 117 simultaneously with actuation ofthe delivery unit 120, as will be described in more detail hereinbelow.

The valve assembly 127 comprises a main, body element 128 which includesa valve seat 129 defining a valve opening 130, and a valve element 131which is movably disposed to the body element 128 between closed andopen positions, as illustrated in FIGS. 3 and 4.

As particularly illustrated in FIG. 3, the body element 128 comprises apivot 135, in this embodiment to one, lower side of the valve seat 129,to which one end 145 of the valve element 131 is pivoted, and a slidingsurface 137, in this embodiment to the other, upper side of the valveseat 129, against which the other end 147 of the valve element 131 isslideable.

The valve element 131 comprises an elongate arm 141, in this embodimenta flexible arm, one end 145, in this embodiment the lower end, of whichis pivoted to the pivot 135 of the body element 128, and the other,upper end 147 of which slideably engages the sliding surface 137 of thebody element 128, and a valve member 149 which is supported by the arm141.

In this embodiment the arm 141 comprises a first, here lower, armsection 151, which is biased, here inwardly, such that, when the valveelement 131 is in the closed, rest position, the lower arm section 151is inclined inwardly relative to the longitudinal axis of the housing115 and engageable by the substance-supply unit 169 when manuallyactuated to move the valve element 131 to the open position, as will bedescribed in more detail hereinbelow.

In this embodiment the arm 141 further comprises a second, here upper,arm section 153, which engages the sliding surface 137 of the bodyelement 128 and acts to bias the valve element 131 to the closedposition.

In this embodiment the valve member 149 comprises a seal 161, in thisembodiment a flexible or resilient element, which acts to close thevalve opening 130 as defined by the valve seat 129 when the valveelement 131 is in the closed position, and a support 163 which supportsa central region of the seal 161.

With this configuration, and referring to FIGS. 6(a) to (c), where theseal 161 is centrally supported, when the valve element 131 is moved tothe open position, the support 163 biases the central region of the seal161, as illustrated in FIG. 6(b), causing the seal 161 to bulgeoutwardly in this central region and thus provide that the seal 161engages the valve seat 129 only at the peripheral edge of the seal 161,until the point is reached when the seal 161 is suddenly and explosivelyreleased from the valve seat 129, as illustrated in FIG. 6(c).

This mode of release is believed to be particularly effective in thepresent application where it is desired to achieve a sudden, initialburst of air flow, in that substantially the entire sealing surface ofthe seal 161 is released in one instant, which compares to analternative mode of a peeling-type release, where a smaller section of asealing surface is released, followed by the remainder of the sealingsurface, which tends to provide a smaller initial burst pressure.

In this embodiment the delivery unit 120 comprises an outlet unit 167for delivering substance into the nasal airway of the subject, and asubstance-supply unit 169 for delivering substance to the outlet unit167.

In this embodiment the valve assembly 127 provides for a pre-actuationefficiency of less than 5 L/min when a user is developing an exhalationpressure of 3 kPa, preferably less than 5 L/min when a user isdeveloping an exhalation pressure of 10 kPa, more preferably less than 1L/min when a user is developing an exhalation pressure of 3 kPa, stillmore preferably less than 1 L/min when a user is developing anexhalation pressure of 10 kPa, yet more preferably substantially no flowwhen a user is developing an exhalation pressure of 3 kPa, and still yetmore preferably substantially no flow when a user is developing anexhalation pressure of 10 kPa; the pre-actuation efficiency being ameasure of the volume of air which escapes from the device prior toactuation as a fraction of the volume of air delivered into themouthpiece 119.

In this embodiment the delivery device is configured to provide apost-actuation efficiency of at least 80% at a flow rate of 50 L/min andan exhalation pressure of 3 kPa, preferably at least 85% at a flow rateof 50 L/min and an exhalation pressure of 3 kPa, more preferably atleast 88% at a flow rate of 50 L/min and an exhalation pressure of 3kPa, and yet more preferably at least 90% at a flow rate of 50 L/min andan exhalation pressure of 3 kPa; the post-actuation efficiency being ameasure of the volume of air delivered from the nosepiece 117 as afraction of the volume of air delivered into the mouthpiece 119.

FIG. 7 illustrates, for one exemplary device, plots of the flow rates atthe nosepiece 117 and the mouthpiece 119 and the pressure at themouthpiece 119.

In this embodiment the pre-actuation efficiency of 1 L/min at apre-actuation pressure of 5 kPa.

In this embodiment the post-actuation efficiency is 88% at a flow rateof 57.1 L/min.

In this embodiment, the valve element 131 provides for a burst of airflow on opening thereof, having a first, initial burst phase followed bya second, extended burst phase, wherein the peak flow rate in theinitial burst phase has a higher flow rate than the average flow rate inthe extended burst phase, and the extended burst phase is ofsubstantially greater duration than the initial burst phase.

In this embodiment the peak flow rate in the initial burst phase is atleast 10%, preferably at least 15%, and more preferably at least 20%,greater than that of the average flow rate of the extended burst phasein a period corresponding to ten times the duration of the period inwhich substance is delivered from the nosepiece 117 by the delivery unit120.

In this embodiment the delivery unit 120 provides a spray whichcommences 54 ms after opening of the sealing member 149 and terminates134 ms after opening of the sealing member 149.

In one embodiment the delivery unit 120 provides for delivery ofsubstance subsequent to opening of the sealing member 149.

In one embodiment the delivery unit 120 provides for delivery ofsubstance in a period less than about 250 ms from opening of the sealingmember 149, preferably less than about 200 ms from opening of thesealing member 149, more preferably less than about 150 ms from openingof the sealing member 149, and still more preferably more preferablyless than about 100 ms from opening of the sealing member 149.

In one embodiment the delivery unit 120 provides for delivery ofsubstance commencing less than about 150 ms subsequent to opening of thesealing member 149, preferably less than about 100 ms subsequent toopening of the sealing member 149, still more preferably less than about50 ms subsequent to opening of the sealing member 149, yet morepreferably less than more than about 25 ms subsequent to opening of thesealing member 149, still more preferably less than about 15 mssubsequent to opening of the sealing member 149.

In this embodiment the outlet unit 167 comprises a nozzle 171 fordelivering substance to the nasal airway of the subject. In thisembodiment the nozzle 171 is configured to provide an aerosol spray. Inan alternative embodiment, for the delivery of a liquid, the nozzle 171could be configured to deliver a liquid jet as a column of liquid.

In a preferred embodiment the distal end of the outlet unit 167 isconfigured to extend at least about 2 cm, preferably at least about 3cm, and more preferably from about 2 cm to about 3 cm, into the nasalcavity of the subject.

In this embodiment the substance supply unit 169 is a pump unit, whichcomprises a substance-containing chamber 173 which contains substanceand extends from the aperture 123 in the housing 115 as the actuatingpart of the substance-supply unit 169, and a mechanical delivery pump175 which is actuatable, here by depression of the substance-containingchamber 173, typically by a finger or thumb of the subject, to deliver ametered dose of substance from the substance-containing chamber 173 tothe outlet unit 167 and from the nozzle 171 thereof, here as an aerosolspray.

In this embodiment the substance-containing chamber 173, when depressedto actuate the substance supply unit 169, engages the lower arm section151 of the arm 141 of the valve element 131, such as simultaneously toprovide for actuation of the substance-supply unit 169 and opening ofthe seal 161 of the valve element 131, whereby substance, here in theform of a spray, and an air flow, here as a burst of air, aresimultaneously delivered to the nasal cavity of the subject.

In this embodiment the mechanical delivery pump 175 is a liquid deliverypump for delivering a metered dose of substance, but in an alternativeembodiment the mechanical delivery pump 175 could be a powder deliverypump, which delivers metered doses of a powdered substance on actuationthereof.

In this embodiment the substance-supply unit 169 is a multi-dose unitfor delivering a plurality of metered doses of substance in successivedelivery operations.

In an alternative embodiment the substance-supply unit 169 could be asingle-dose unit for delivering a single metered dose of substance or aduo-dose unit for delivering two metered doses of substance in twosuccessive delivery operations.

In another alternative embodiment the substance-supply unit 169 couldcomprise a dry powder delivery unit which delivers metered doses of asubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance-supply unit 169could comprise a nebulizer which delivers metered doses of a substance,as an aerosol spray, on actuation thereof.

In still another alternative embodiment the substance-supply unit 169could comprise an aerosol canister for delivering metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In this embodiment the housing 115 further comprises a scaling member181, here an annular seal, in the form of an O-ring, which slideablyreceives the substance-containing chamber 173 of the substance-supplyunit 169, such as to prevent the escape of the delivered air flow fromthe aperture 123 in the housing 115.

In one embodiment the sealing member 181 could be omitted.

FIGS. 8(a) and (b) illustrate a nasal delivery device in accordance witha second embodiment of the present invention.

The delivery device of this embodiment is substantially the same as thedelivery device of the first-described embodiment, and thus, in order toavoid unnecessary duplication of description, only the differences willbe described in detail, with like parts being designated by likereference signs.

The delivery device of this embodiment differs from that of thefirst-described embodiment principally in that the valve member 149 isconfigured such that the support 163 extends across substantially theentire width of the valve opening 130. In this way, the seal 161 is notable to bulge in the manner of the above-described embodiment, and isinstead opened by a peeling action. FIG. 8(a) illustrates the valveassembly 127 in the at rest, non-actuated configuration. FIG. 8(b)illustrates the valve assembly 127 in the actuated configuration.

FIGS. 9(a) and (b) illustrate a nasal delivery device in accordance witha third embodiment of the present invention.

The delivery device of this embodiment is very similar to the deliverydevice of the first-described embodiment, and thus, in order to avoidunnecessary duplication of description, only the differences will bedescribed in detail, with like parts being designated by like referencesigns.

The delivery device of this embodiment differs from that of thefirst-described embodiment principally in that the seal 161 is notsupported by the arm 141, but is instead a separate element, which isdisplaced by movement of the arm 141, as caused by manual actuation ofthe substance-supply unit 169. FIG. 9(a) illustrates the valve assembly127 in the at rest, non-actuated configuration. FIG. 9(b) illustratesthe valve assembly 127 in the actuated configuration.

In this embodiment the seal 161 comprises a flexible element, here inthe form of a flap, and in one embodiment a resilient element, which isengaged by an engagement element 185 on the arm 141.

In this embodiment the engagement element 185 comprises a projectionwhich acts to cause the seal 161 to bulge in the manner of thefirst-described embodiment.

In an alternative embodiment the engagement element 185 could extendacross substantially the width of the valve opening 130, causing theseal 161 to be moved from the valve seat 129 with a peeling action in asimilar manner to the second-described embodiment.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

1-49. (canceled)
 50. A nasal delivery device for delivering substance toa nasal airway of a subject, comprising: a nosepiece for fitting to anasal cavity of a subject; a mouthpiece into which the subject in useexhales; a delivery unit, which comprises an actuation part which ismanually displaceable to actuate the delivery unit to deliver substancefrom the nosepiece; and a valve assembly which is fluidly connected tothe nosepiece and the mouthpiece, wherein the valve assembly comprises abody element and a valve element which is movably disposed to the bodyelement between closed and open configurations by manual displacement ofthe actuation part of the delivery unit to provide for an air flowthrough the nosepiece simultaneously with delivery of substance; whereinthe body element includes a valve seat which defines a valve opening,and the valve element comprises a seal, which has a central region and aperipheral region and acts to close the valve opening when the valveelement is in the closed configuration, and a support which supports thecentral region of the seal, whereby the peripheral region of the sealengages the valve seat when the valve element is in the closedconfiguration and the central region of the seal is deflected, relativeto the peripheral region of the seal, when the valve element is moved tothe open configuration, thereby allowing for sudden release of the seal.51. The delivery device of claim 50, wherein the body element includes apivot, and the valve element comprises an arm having first and secondends, with the first end of the arm being pivoted to the pivot of thebody element between the closed and open configurations.
 52. Thedelivery device of claim 51, wherein the arm is at least in partresilient.
 53. The delivery device of claim 51, wherein the body elementincludes a sliding surface, against which the second end of the arm isslideable.
 54. The delivery device of claim 50, wherein the valveassembly, on opening of the valve element, provides for a burst of airflow, having a first, initial burst phase followed by a second, extendedburst phase, wherein the peak flow rate in the first burst phase has ahigher flow rate than the average flow rate in the second burst phase,and the second burst phase is of substantially greater duration than thefirst burst phase.
 55. The delivery device of claim 54, wherein the peakflow rate in the first burst phase is at least 10% greater than that ofthe average flow rate of the second burst phase in a periodcorresponding to ten times the duration of the period in which substanceis delivered from the delivery unit.
 56. The delivery device of claim54, wherein the peak flow rate in the first burst phase is at least 15%greater than that of the average flow rate of the second burst phase ina period corresponding to ten times the duration of the period in whichsubstance is delivered from the delivery unit.
 57. The delivery deviceof claim 54, wherein the peak flow rate in the first burst phase is atleast 20% greater than that of the average flow rate of the second burstphase in a period corresponding to ten times the duration of the periodin which substance is delivered from the delivery unit.
 58. The deliverydevice of claim 50, wherein the delivery unit provides for delivery ofsubstance subsequent to opening of the valve element.
 59. The deliverydevice of claim 58, wherein the delivery unit provides for delivery ofsubstance in a period less than about 250 ms from opening of the sealingmember.
 60. The delivery device of claim 58, wherein the delivery unitprovides for delivery of substance in a period less than about 200 msfrom opening of the sealing member.
 61. The delivery device of claim 58,wherein the delivery unit provides for delivery of substance in a periodless than about 150 ms from opening of the sealing member.
 62. Thedelivery device of claim 58, wherein the delivery unit provides fordelivery of substance in a period less than about 150 ms from opening ofthe sealing member.
 63. The delivery device of claim 58, wherein thedelivery unit provides for delivery of substance in a period less thanabout 100 ms from opening of the sealing member.
 64. The delivery deviceof claim 50, wherein the delivery unit provides for delivery ofsubstance commencing less than about 150 ms subsequent to opening of thevalve element.
 65. The delivery device of claim 64, wherein the deliveryunit provides for delivery of substance commencing less than about 100ms subsequent to opening of the valve element.
 66. The delivery deviceof claim 64, wherein the delivery unit provides for delivery ofsubstance commencing less than about 50 ms subsequent to opening of thevalve element.
 67. The delivery device of claim 64, wherein the deliveryunit provides for delivery of substance commencing less than about 25 mssubsequent to opening of the valve element.
 68. The delivery device ofclaim 64, wherein the delivery unit provides for delivery of substancecommencing less than about 15 ms subsequent to opening of the valveelement.
 69. The delivery device of claim 50, wherein the delivery unitcomprises a mechanical delivery pump which is actuatable by depressionof the actuation part.